7-26346464-G-A

Position:

• chr7-26346464-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_013322.3(SNX10):​c.22G>A​(p.Glu8Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,453,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SNX10 NM_013322.3 missense, splice_region
• Scores: Splicing: ADA: 0.6281
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

Genes affected

SNX10 (HGNC:14974): (sorting nexin 10) This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein does not contain a coiled coil region, like some family members. This gene may play a role in regulating endosome homeostasis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

SNX10 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a region_of_interest Required for interaction with ATP6V1D (size 117) in uniprot entity SNX10_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_013322.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2070553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNX10	NM_013322.3	c.22G>A	p.Glu8Lys	missense_variant, splice_region_variant	2/7	ENST00000338523.9	NP_037454.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNX10	ENST00000338523.9	c.22G>A	p.Glu8Lys	missense_variant, splice_region_variant	2/7	1	NM_013322.3	ENSP00000343709.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453578 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 723734

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1358690). This variant has not been reported in the literature in individuals affected with SNX10-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 8 of the SNX10 protein (p.Glu8Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.25	T;.;.
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.59	N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.3	.;N;N
REVEL	Benign	0.12
Sift	Benign	0.20	.;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.59
MutPred		0.48		Gain of methylation at E8 (P = 6e-04);Gain of methylation at E8 (P = 6e-04);Gain of methylation at E8 (P = 6e-04);
MVP		0.45
MPC		0.32
ClinPred		0.65	D
GERP RS		4.9
Varity_R		0.37
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.63
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1788391863; hg19: chr7-26386084;